The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electro-encephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery–Åsberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity–as reflected by increased SWA, individual slow wave parameters and plasma BDNF–is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response.

Anandamide (AEA) and ⌬ 9 -tetrahydrocannabinol (THC) are endogenous and exogenous ligands, respectively, for cannabinoid receptors. Whereas most of the pharmacological actions of cannabinoids are mediated by CB1 receptors, there is also evidence that these compounds can produce effects that are not mediated by the activation of identified cannabinoid receptors. Here, we report that THC and AEA, in a CB1 receptorindependent manner, cause a significant potentiation of the amplitudes of glycine-activated currents (I Gly ) in acutely isolated neurons from rat ventral tegmental area (VTA) and in Xenopus laevis oocytes expressing human homomeric (␣1) and heteromeric (␣1␤1) subunits of glycine receptors (GlyRs). The potentiation of I Gly by THC and AEA is concentration-dependent, with respective EC 50 values of 86 Ϯ 9 and 319 Ϯ 31 nM for ␣1 homomeric receptors, 73 Ϯ 8 and 318 Ϯ 24 nM for ␣1␤1 heteromeric receptors, and 115 Ϯ 13 and 230 Ϯ 29 nM for native GlyRs in VTA neurons. The effects of THC and AEA are selective for I Gly , because GABA-activated current in VTA neurons or in X. laevis oocytes expressing ␣2␤3␥2 GABA A receptor subunits were unaffected by these compounds. The maximal potentiation by THC and AEA was observed at the lowest concentration of glycine; with increasing concentrations of glycine, the potentiation significantly decreased. The site for THC and AEA seems to be distinct from that of the alcohol and volatile anesthetics. The results indicate that THC and AEA, in pharmacologically relevant concentrations, directly potentiate the function of GlyRs through an allosteric mechanism.

Background The rapid clinical antidepressant effects of the glutamatergic modulator ketamine may be due to its ability to restore synaptic plasticity and related effects on sleep-wake and circadian systems. Preclinical studies indicate that ketamine alters expression of circadian clock-associated molecules, and clinical studies of ketamine on plasticity-related biomarkers further suggest an association with sleep slow waves and sleep homeostasis. Methods Wrist activity monitors were used to examine the pharmacologic and rapid antidepressant effects of ketamine on markers of circadian timekeeping (amplitude and timing) in mood disorders. Circadian amplitude and timing of activity at baseline, post-infusion Day1 (D1), and Day3 (D3) were measured in 51 patients with major depressive disorder (MDD) or bipolar disorder (BD). Results Compared with either placebo or baseline, a mood-independent decrease of the central circadian value (mesor) was present on D1 after ketamine treatment. Mood-associated circadian effects between rapid (D1) responders and non-responders were found at baseline, D1, and D3. At baseline, a phase-advanced activity pattern and lower mesor distinguished subsequent responders from non-responders. On D1, ketamine non-responders had a lower mesor and a blunted 24-hour amplitude relative to baseline. On D3, patients with a persisting clinical response exhibited a higher amplitude and mesor compared with non-responders. Conclusions The findings are the first to demonstrate an association between ketamine’s clinical antidepressant effects and circadian timekeeping. The results suggest that trait-like circadian activity patterns indicate rapid mood response to ketamine, and that mediators of continuing ketamine-induced mood changes include altered timing and amplitude of the circadian system.

PurposeThis study examined the links between 24-hour activity patterns (specifically, amplitude and timing of wrist activity) and the persisting qualities of clinical antidepressant response to the glutamatergic modulator ketamine.MethodsTwenty-four-hour activity patterns were compared across 5 days of 24-hour activity rhythms in patients with major depressive disorder who displayed either a brief antidepressant response (24–48 hours), a continued antidepressant response (>72 hours), or no antidepressant response to ketamine. These postinfusion-response profiles were then used retrospectively to examine cohort-specific fitted parameters at baseline, postinfusion day 1 (D1), and postinfusion D3.ResultsRelative to the nonresponders, the cohort experiencing a brief antidepressant response had blunted 24-hour amplitude that extended from baseline through D3 and postketamine phase advance of activity on D1 that reverted to baseline on D3. Relative to the nonresponders, the cohort experiencing a continued antidepressant response to ketamine had phase-advanced activity at both baseline and D1, as well as increased amplitude on D1 and D3.ConclusionTaken together, the results suggest that the time course of antidepressant response to ketamine is influenced by underlying biological differences in motor activity timekeeping. These differences may provide clues that link durable mood response with the molecular machinery of the circadian system, thus leading to more effective interventions. In addition, biomarkers of preinfusion motor activity (eg, amplitude, timing) may be useful for recommending future individualized treatment interventions, to the extent that they help identify patients who may relapse quickly after treatment.

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